Xanthine oxidase is known as an enzyme which converts hypozanthine to xanthine and further converts thus-formed zanthine to uric acid. Although most mammals have uricase, humans and chimpanzees do not, thereby uric acid is known to be the final product of purine metabolism (S. P. Bruce, Ann. Pharm., 2006, 40, 2187˜2194). Sustained elevation of blood concentration of uric acid causes various diseases, representatively including gout.
As described above, gout is caused by an elevated level of uric acid in the body, indicating the condition in which uric acid crystals accumulated in cartilage, ligament and surrounding tissue induce severe inflammation and pain. Gout is a kind of inflammatory articular disease, and its incidence rate has steadily increased during past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587˜2590).
From the 1960s to the mid-1990s, gout patients in the West exhibited an astonishing increase of about 200˜300%, mainly in males. The increased rate of gout patients can be traced to obesity, aging, kidney function decline, hypertension, etc. The incidence rate of gout appears to be a level of about 1.4/1,000 persons, but it also depends on the uric acid level. That is, while the incidence rate of gout is 0.5% in a patient group with a blood uric acid level of 7.0 mg/dl or more, the incidence rate of gout is 5.5% in a patient group with a uric acid level of 9.0 mg/dl or more (G. Nuki, Medicine, 2006, 34, 417˜423). Considering the incidence rate as described above, blood uric acid level is found to be an important causative factor for gout. In addition, dietary habits, alcohol, lipid and obesity can serve as important inducing factors of gout. Recently, the correlation of uric acid with heart failure, hypertension, diabetes, kidney diseases and cardiovascular diseases has been extensively investigated by many researchers, and the importance of uric acid control has been increased (D. I. Feig et al., N. Eng. J. Med, 2008, 23, 1811˜1821). In addition, as an inhibitor of xanthine oxidase, allopurinol is known to have an effect on ulcerative colitis (Aliment. Pharmacol. Ther. 2000, 14, 1159˜1162; WO 2007/043457).
Allopurinol was a unique drug for the treatment of gout for 40 years, until febuxostat was approved as an arthrifuge in USA in 2009 (Brain Tomlinson, Current Opin. Invest. Drugs, 2005, 6, 1168˜1178). Allopurinol is known to be a non-specific inhibitor for various enzymes that are involved in purine and pyrimidine metabolism, and it has a Ki of 700 nM for xanthine oxidase (Y. Takano et al., Life Sciences, 2005, 76, 1835˜1847). Allopurinol is immediately oxidized to oxypurinol by xanthine oxidase, and this metabolite is known to act as a potent inhibitor for xanthine oxidase.
However, it is known that allopurinol causes gastrointestinal side effects and skin rash and exhibits poor compliance in the case of long-term administration. Especially among patients receiving allopurinol, the side effect of Stevens-Johnson syndrome is reported, at a low rate but it is unpredictable and lethal (Felix Arellano et al., Ann. Pharm., 1993, 27, 337˜43). This serious side effect is known to accompany necrocytosis in the skin and mouth mucosa, and without proper treatment about 25% of patients may die as a result.
Thus, in order to develop novel xanthine oxidase inhibitors various researches have been conducted resulting in numerous patent publications (for example, WO 1992/009279, WO 1998/018765, WO 2007/004688, WO 2007/043457, WO 2008/126770, WO 2008/126898, WO 2008/126899).
Among these, WO 1998/018765 describes the inhibitory effect of pyrazoles and phenyl derivatives against xanthine oxidase, and WO 2008/126898 reports that indole compounds exhibit an inhibitory effect against xanthine oxidase.